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O‑Β‑D‑Glucopyranoside on P2Y12 and Thromboxane A2 Receptor‑Mediated Amplification of Platelet Activation in Vitro

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O‑Β‑D‑Glucopyranoside on P2Y12 and Thromboxane A2 Receptor‑Mediated Amplification of Platelet Activation in Vitro INTERNATIONAL JOURNAL OF MOleCular meDICine 42: 615-624, 2018 Inhibitory effects of luteolin‑4'‑O‑β‑D‑glucopyranoside on P2Y12 and thromboxane A2 receptor‑mediated amplification of platelet activation in vitro HUANJUN XU1, HONG LU2, XIAOCUI ZHU1, WEI WANG1, ZHOUMIAO ZHANG1, HUIZHENG FU3, SHUANGCHENG MA4, YUEHUA LUO3 and JIANJIANG FU1 1Department of Pharmacology, School of Pharmacy; 2Network and Educational Technology Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004; 3Jiangxi Provincial Institute for Drug Control, Nanchang, Jiangxi 330029; 4National Institutes for Food and Drug Control, Beijing 100050, P.R. China Received November 1, 2017; Accepted March 27, 2018 DOI: 10.3892/ijmm.2018.3634 Abstract. Platelet activation and subsequent accumulation may be associated with its dual-receptor inhibition on P2Y12 at sites of vascular injury are central to thrombus formation, and TP receptors. which is considered to be a trigger of several cardiovascular diseases. Callicarpa nudiflora (C. nudiflora) Hook is a Introduction traditional Chinese medicinal herb for promoting blood circulation by removing blood stasis. In our previous study, Platelets are small, a nucleate blood cells, the major role of several compounds extracted from this herb, including which is in hemostasis and thrombosis owing to their capacity luteolin-4'-O-β‑D‑glucopyranoside (LGP), were revealed to adhere to damaged blood vessels and to accumulate at sites to exert inhibitory effects on adenosine diphosphate of injury (1). However, platelets are also important contributors (ADP)-induced platelet aggregation. The aim of present study to thrombotic disorders, including atherothrombosis, which was to confirm these antiplatelet effects and elucidate the are the final events complicating cardiovascular diseases (2‑4). potential mechanisms. Using a platelet-aggregation assay, it Upon vascular injury, platelets are exposed to the subendothe- was revealed that LGP significantly inhibited platelet aggre- lium, and several agonists, including adenosine diphosphate gation induced by ADP, U46619 and arachidonic acid. It was (ADP) and thrombin, are generated at the injury site, which also found that LGP exhibited marked inhibitory effects on can stimulate platelet adhesion, activation and aggregation. the activation of αIIbβ3 integrin, the secretion of serotonin from Adherent, activated platelets recruit additional platelets to the granules, and the synthesis of thromboxane A2. In addition, growing thrombus (5,6). The uncontrolled progression of these the results showed that LGP suppressed Ras homolog family processes through a series of self‑sustaining amplification member A and phosphoinositide 3-kinase/Akt/glycogen loops can initiate unrestrained platelet activation and aggrega- synthase kinase 3β signal transduction. Data from a radio- tion, and eventually lead to thromboembolic events (7,8). It has labeled ligand-binding assay indicated that LGP exhibited been demonstrated clinically that the use of antiplatelet agents apparent competing effects on thromboxane receptor (TP) to prevent and/or reverse platelet aggregation is a successful and P2Y12 receptors. In conclusion, the data presented here strategy for the prevention of thrombosis (7,8). However, demonstrated that LGP, a natural compound from C. nudiflora due to their disturbance of the thromboregulatory balance, Hook, inhibited the development of platelet aggregation and existing antiplatelet drugs can cause severe side effects, the amplification of platelet activation. These inhibitory effects majority of which limit the efficacy and safetyof these drugs. Uncontrolled hemorrhage is the most frequent side effect of antithrombotics/antiplatelets (9,10). Therefore, understanding the molecular mechanisms of platelet activation and identi- fying novel techniques for platelet inhibition remain critically important. Correspondence to: Dr Jianjiang Fu, Department of Pharmacology, Natural products remain a major resource and have become School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, 818 Meiling Road, Nanchang, Jiangxi 330004, P.R. China increasingly important for novel drug identification. The E-mail: [email protected] Callicarpa genus includes ~190 extant species (11). Among these, there are >10 medical herbs, and the majority of these Key words: platelet activation, P2Y12 receptor, thromboxane A2 have hemostasis-associated usage (11). Callicarpa nudiflora receptor, Callicarpa nudiflora, luteolin-4'-O-β‑D‑glucopyranoside (C. nudiflora) Hook, which is one of the medical herbs of Callicarpa with a long history, is used for eliminating stasis in order to subdue swelling and hemostasis (11). According 616 XU et al: ANTIPLATELET EFFECTS OF LGP to traditional Chinese medicine theory, eliminating stasis to subdue swelling is similar to the antithrombotic effect. Led by these concepts, the present study hypothesized that antiplatelet activities may contribute to the traditional usage of this plant. In our previous study, hundreds of constituents were screened, including several derivatives of luteolin. It was found that two novel triterpenoids, extracted from the leaves of C. nudiflora, showed inhibitory effects on ADP-induced platelet activation (12,13). In the present study, it was shown that one of the derivatives of luteolin, 1,6-di-O-caffeoyl-β‑D‑glucopyranoside (LGP) exhibited potent inhibitory effects on platelet activation, and it was Figure 1. Molecular structure of luteolin-4'-O-β‑D‑glucopyranoside. demonstrated that the effects of this natural compound may be mediated by dual receptor antagonism on P2Y12 receptor and thromboxane A2 (TXA2) receptor (TP). The PRP was adjusted to a platelet count of 400x109 platelets/l Materials and methods by diluting in PPP. Drugs and chemicals. Luteolin-4'-O-β‑D‑glucopyranoside Platelet aggregation. Platelet aggregation in 96-well plates was (LGP) was isolated from the leaves of C. nudiflora Hook measured using a modified light transmission method (14,15). and its molecular structure is shown in Fig. 1. The purity Briefly, the PRP (400x109 platelets/l) was incubated with 40, of LGP was ≥95%, as determined by high‑performance 80 and 160 µM of LGP, antagonists (positive controls) or liquid chromatography. A stock solution was prepared by dissolvent for 15 min at 37˚C, respectively. The optical density dissolving the LGP in 100% dimethyl sulfoxide (DMSO) (OD) was then determined at 595 nm and marked as OD1. and was used throughout the investigation. The final DMSO Platelet aggregation was induced by the following agonists: concentration did not exceed 0.1%. ADP, arachidonic acid ADP (10 µM), U46619 (1 µM) or AA (600 µM), and OD (OD2) (AA), ticagrelor (an antagonist of the P2Y12 receptor) and was determined again at 595 nm every 30 sec for 15 min, BM-531 (an antagonist of the TP receptor), were purchased with 15 sec incubation and 15 sec shaking between readings. from Sigma-Aldrich; EMD Millipore (Billerica, MA, USA). In addition, the OD value at 595 nm was determined for the U46619 was the product of Tocris Bioscience (Bristol, UK). same volume of PPP, and was marked as OD3. All experi- [3H]-2-methylthioadenosine diphosphate ([3H]-2-MeS-ADP) ments were performed at least three times. The percentage and [3H] SQ-29548 were purchased from GE Healthcare Life of aggregation was calculated using the absorbance of PRP Sciences (Chalfont, UK) and PerkinElmer, Inc. (Waltham, without agonist as 0% aggregation and the absorbance of PPP MA, USA), respectively. as 100% aggregation. The relative aggregation was expressed using the following formula: Relative aggregation (%)=[(OD1- Animals. A total of 80 female Sprague‑Dawley rats (aged OD2)/(OD1-OD3)] x100. 6-8 weeks old and weighing 180-220 g) were obtained from Vital River Laboratories (Beijing, China) and maintained Activated αIIbβ3 integrin abundance. αIIbβ3 integrin is under pathogen-free conditions in the Animal Center of Jiangxi expressed on the surface of platelets, which reflects platelet University of Traditional Chinese Medicine (Nanchang, activation or secretion from platelet granules. This was China). All the animals were maintained in a 12 h light/dark determined by the measurement of fluorescent agent‑labeled cycle at room temperature (25±2˚C) in 60% humidity. The antibody binding, as described previously (16,17). For animals were allowed water ad libitum and were fed a standard measurement of the expression of αIIbβ3 integrin, briefly, laboratory diet. The protocol used for animal experiments 50 µl activated platelets (400x109 platelets/l) were pretreated (JZAEC‑2016-0031) was approved by the Animal Ethics for 15 min with DMSO or the indicated concentrations (20, Committees of Jiangxi University of Traditional Chinese 40, 80 and 160 µM) of LGP, and then fixed for 30 min in Medicine, and all animal experiments were performed in strict 0.5% paraformaldehyde. Following washing once in incu- accordance with the requirements of this protocol. bation buffer, the fixed platelets were added into 96-well plates, and incubated with Oregon Green‑labeled fibrinogen Preparation of rat platelets. Blood was collected from the (Molecular Probes; Thermo Fisher Scientific, Inc., Waltham, abdominal aorta of anesthetized rats into a vacuum blood MA, USA) for 15 min at room temperature without shaking. collection tube, which allowed 10% blood volume with 3.8% The total fluorescence was determined by measuring the fluo- sodium citrate as anticoagulant. The citrated blood was then rescence
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